Packaging system for pharmaceutical compositions and kit for intravenous administration

ABSTRACT

The invention refers to a new system for packaging pharmaceutical compositions comprising active principles that may be administered intravenously, in particular it concerns a system for packaging in bottles which makes it possible to ensure the complete transfer of the content of the bottle into the liquid for intravenous infusion and at the same time prevent any accidental contact with the active principle by the health-care personnel preparing said intravenous infusion, and a complete kit for intravenous administration.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.12/443,058, filed Apr. 16, 2009, which is the U.S. national phase ofInternational Application No. PCT/IB2007/002857, filed Sep. 28, 2007,which designated the U.S. and claims priority to Italian Application No.MI2006A001881, filed Sep. 29, 2006, and Italian Application No.MI2007A000635, filed Mar. 29, 2007, the entire contents of each of whichare hereby incorporated by reference.

SUMMARY OF THE INVENTION

The present invention refers to a new system for packagingpharmaceutical compositions comprising active principles that may beadministered intravenously, in particular it concerns a system forpackaging in bottles which makes it possible to ensure the completetransfer of the content of the bottle into the liquid for intravenousinfusion and at the same time prevent any accidental contact with theactive principle by the health-care personnel preparing said intravenousinfusion. More particularly, the invention refers to a new system forpackaging pharmaceutical compositions comprising Tacrolimus and otherhighly active drugs.

The invention concerns a kit for the parenteral administration ofmedicines which comprises said packaging system.

Technical Context

Some highly active drugs, such as anti-tumour, immunosuppressants,antiviral drugs, some hormone derivatives, are considered potentiallydangerous for the health-care personnel who have to handle them at thetime or administration. For this reason, in the United States, the NIOSH(National Institute for Occupational Safety and Health) publishesguidelines for protecting the health and safety of health-care workers(www.cdc.gov/niosh) and lists the dangerous active principles for whichparticular attention is required during administration, such as the useof gloves and eye protection when opening the drug package (vial orsimilar).

In many cases these drugs are administered intravenously, either becauseof the intrinsic characteristics of the active principle or when thepatient's conditions do not allow them to be administered by mouth.

The pharmaceutical compositions intended for intravenous administrationmust be transferred from the pack in which they are sold into a suitablecontainer holding the liquid for infusion. The transfer is generallymade by taking said compositions (when possible already in a solution orto be dissolved or diluted with an appropriate solvent at the moment ofuse) by means of a syringe and injecting the liquid composition thusobtained into the container holding the liquid for infusion. This typeof transfer presents several inconveniences, including the risk for thehealth-care personnel of accidental pricking or of contact with the drugwhich, as explained above, may be extremely toxic or dangerous. Saidtransfer also presents the risk of losing part of the drug to beadministered, which often remains in the package, as it is difficult toextract a liquid completely with a syringe, for example from an ampoule.This possibility, which is quite frequent, may have extremely seriousconsequences. For this reason pharmaceutical companies tend to minimisethe risk of administering too little with respect to the prescribedamount by means of “overdosing”, that is adding an extra quantity ofactive principle to the pharmaceutical composition too be sold. Thisoverdosing is generally around 10%, but in some particular cases it maybe as much as 20%. Besides the waste of active principles, oftenextremely expensive, this solution involves an opposite risk, that isthe danger of administering to the patient an amount of drug higher thanthat necessary for the therapy. It can easily be understood that,especially for highly active drugs, this risk is unacceptable for thepatient's health.

Another problem connected with the use of ampoules lies in the cost andcomplexity of production. The process for producing ampoules is in factmuch more expensive than that of producing bottles and involves riskslinked with the flammability of the solvents used as vehicles for theactive principles.

Technology has recently developed means for trying to overcome at leastpart of the inconveniences listed above. In particular, connectorsequipped with at least two perforating spikes (known as spikes) havebeen designed and marketed, suited to put directly into connection thecontainer holding the liquid for infusion and the package of thepharmaceutical composition, which in this case is generally a bottlesealed with an appropriate rubber cap. These connectors thereforeperforate the cap of the container holding the liquid for infusion onone side and the cap of the bottle holding the composition on the otherand said composition can be transferred by means of the so-calledwash-out of the bottle by the liquid for infusion which is pushedupwards by compression of the infusion container, which in this case ismade of collapsible material. These means are marketed for example bythe company B. Braun Melsungen AG, Germany.

This combination makes it possible to avoid the inconvenience related tothe risk of accidental pricking or of contact with the drug forhealth-care personnel, but it does not actually solve the problem of thecomplete transfer of the pharmaceutical composition into the liquid tobe administered by infusion, nor the problem of overdosing of the drug.

In fact, in pharmaceutical compositions for infusion, in particularthose including the highly active drugs mentioned above, the activeprinciples are often dissolved using lipophilic substances and they donot dissolve easily in conventional liquids for infusion; it has beenverified that the transfer by “washing out” the bottle with the liquidfor infusion, which is of necessity composed of an aqueous solutionmixable with said lipophilic substances, is often incomplete.

OBJECTS OF THE INVENTION

The object of the present invention is to overcome all theinconveniences of the known technique, providing a system for packagingin bottles pharmaceutical compositions comprising active principles thatmay be administered intravenously and a complete kit for its use, whichmakes it possible to ensure the complete transfer of the content of thebottle into the liquid for intravenous infusion and which is safe forthe health-care personnel who have to administer it.

Another object of the present invention is to reduce the costs and thedangers indicated above, connected with the production of ampoules.

Another object of the present invention is to provide a system forpackaging in bottles Tacrolimus and other drugs that may be administeredintravenously and a complete kit for its use, which at the same timemakes it possible to safeguard the health of the health-care personneland to administer the exact quantity of the necessary active principle,reducing both the waste of expensive drugs and the risk of overdosingfor the patient.

It has surprisingly been observed that the size of the bottle is ofcritical importance for the correct transfer of the pharmaceuticalcomposition that it contains into the container for infusion. It has infact been found that the identification of a suitable size of the bottleis indispensable for the “washing out” described above to be effectivefor the complete transfer of the drug.

The authors of the present invention have highlighted, for the firsttime, the fundamental role played by the size of the bottle for theefficacy of the transfer of the pharmaceutical composition to betransferred into a liquid for infusion using the system described above,with particular reference to Tacrolimus and other drugs dissolved inlipophilic substances and that do not dissolve easily in the liquids forinfusion. This critical aspect had never been considered before in theprior art.

It has now unexpectedly been observed that the washing out of a bottleof the type described above, containing a pharmaceutical composition tobe administered in a liquid for intravenous infusion, is much moreeffective when the size of said bottle is calculated in such a way as toallow a large empty volume, that is if it is not almost entirely filledwith the pharmaceutical composition. This observation is in sharpcontrast with the current practices of pharmaceutical technology, whichtend to leave very little empty volume inside the package of apharmaceutical composition, above all if of a liquid type. For example,the active principle Tacrolimus is sold in ampoules with a capacity ofonly 2 ml, which contain 1 ml of pharmaceutical composition, so they arehalf full.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 shows a particularly advantageous embodiment of the kit of theinvention, at the moment of transfer of the pharmaceutical compositionfrom the dosage unit (b) to the container (a) by means of a connectorwith two spikes (c).

DESCRIPTION OF THE INVENTION

So, according to one of its aspects, the invention concerns a packagingsystem for holding a pharmaceutical composition to be administered in aliquid for intravenous infusion, characterised in that said packagingsystem is a bottle which comprises said pharmaceutical composition andan empty volume of more than 80% of the total volume of the bottle,preferably ranging from 80% to 99%, advantageously from 80% to 95%, forexample which is around 85% of the total volume of the bottle.

According to the present invention, the term “pharmaceuticalcomposition” means a drug formulated with one or more pharmaceuticallyacceptable vehicles, ready for transfer into the liquid for intravenousinfusion. So, in the case of drugs which require pre-dilution with acosolvent prior to transfer into the liquid for intravenous infusion,for example docetaxel, the term “pharmaceutical composition” means themixture of the concentrate with the cosolvent.

According to the present invention, the term “liquid for intravenousinfusion” means any conventional solution for intravenous infusion, forexample a saline physiological solution or a physiological solutioncontaining glucose.

According to the present invention, the term “bottle” means a containerholding a pharmaceutical composition, closed with a rubber cap, whichmay be pierced with needles or conventional piercing spikes. Thesebottles are available on the market in different sizes.

According to the present invention, the dimensions of the bottle aredefined as “capacity”, where the term “capacity” indicates the volume ofthe bottle available as generally indicated by the manufacturer and notthe “to the brim” volume of the bottle. So, according to the presentinvention, when mentioning for example a 7 ml bottle, it means a bottlethat the manufacturer declares has a capacity of 7 ml but which, when“brim full”, contains even more than 8 ml, for example 8.4.

According to an advantageous embodiment of the invention, said bottleshall be made of glass, transparent or amber-coloured depending on thelight-sensitivity of the active principle, and preferably it shall havean opening of the DIN/ISO type (about 22 mm), a characteristic whichallows good compatibility with the majority of conventional connectors.

According to the present invention, the term “empty volume” (or alsohead space) means the volume inside the bottle not occupied by thepharmaceutical composition. The empty volume percentages are given herein terms of a percentage with respect to the capacity of the bottle, insuch a way that the sum of the percentage of the volume of thecomposition and of the percentage of the empty volume is always 100%.

According to a preferred aspect of the present invention, said emptyvolume is chosen as a function of the solubility of the active principleand/or of the composition. According to a preferred aspect of thepresent invention, said pharmaceutical composition is a pharmaceuticalcomposition comprising a highly active drug dissolved in a lipophilicsubstance.

According to a preferred aspect of the present invention, saidpharmaceutical composition is a pharmaceutical composition comprising ahighly active drug dissolved in a lipophilic substance.

According to a particularly preferred embodiment of the invention, saidpharmaceutical composition is a pharmaceutical composition comprising adrug chosen among immunosuppressants, anti-tumour drugs and hormones.

According to a particularly preferred embodiment of the invention, saidpharmaceutical composition is a pharmaceutical composition comprising adrug chosen among tacrolimus, cyclosporine, alkylating agents(carmustine, busulfan), docetaxel, paclitaxel, teniposide, pentamidineand valrubicin.

According to another of its aspects, the invention concerns a packagingsystem for a pharmaceutical composition to be administered in a liquidfor intravenous infusion characterised in that said packaging is abottle having a capacity between 5 and 10 ml and said pharmaceuticalcomposition comprises as active principle tacrolimus in apharmaceutically acceptable oily vehicle.

According to a particularly preferred embodiment of this last aspect ofthe invention, said pharmaceutical composition comprises 5 mg oftacrolimus dissolved in 1 ml of solvent composed of 200 mg ofpolyoxyethylenated hydrogenated castor oil (HCO-60) and ethanol, forexample absolute ethanol or anhydrous ethanol USP 80.0% v/v, q.s. to 1ml.

According to a particularly preferred embodiment of the invention, saidpharmaceutical composition comprises from 0.1 to 0.5 mg, preferablyabout 0.25 mg of citric acid, 5 mg of tacrolimus dissolved in 1 ml ofsolvent composed of 200 mg of polyoxyethylenated hydrogenated castor oil(HCO-60) and ethanol, for example absolute ethanol or anhydrous ethanolUSP 80.0% v/v, q.s. to 1 ml.

According to another particularly preferred embodiment thepharmaceutical compositions comprising as active principle 5 mg oftacrolimus, with or without citric acid, are contained in a bottlehaving a capacity from 6 to 9 ml, advantageously of 7 ml, the emptyspace therefore amounting to 85.7%.

If necessary or desired, the pharmaceutical compositions may be packedaccording to the system of the invention in an inert atmosphere, forexample in an atmosphere of nitrogen, argon or CO₂.

For the use of the packaging system of the invention, the bottle in usedin combination with connectors provided with at least two perforatingspikes (known as spikes), suited to put the inside of the bottledirectly in contact with the container holding the liquid for infusion.The container for infusion shall be made of collapsible material andadvantageously compatible with the pharmaceutical composition and theactive principle to be administered, for example in a material otherthan PVC if oily vehicles are used or drugs incompatible with PVC.

According to the present invention, the term “collapsible material”means a material that may be manually compressed to make the liquid forinfusion come out through the spikes of the connector described above.

FIG. 1 shows a particularly advantageous embodiment of the kit of theinvention, at the moment of transfer of the pharmaceutical compositionfrom the dosage unit (b) to the container (a) by means of a connectorwith two spikes (c).

In practice, a container holding a liquid for infusion as defined aboveis engaged on one end of a connector equipped with at least two spikes,one of which penetrates inside the rubber cap of said container; then abottle of the packaging system of the invention, after removal of themetal cap usually present on top of the rubber cap, is engaged, upsidedown, on the other end of the above-mentioned connector, causing theperforation of the rubber cap.

By applying a light pressure on the container in collapsible material,the liquid for infusion passes through the two spikes and flows into thebottle, “washing it out” (FIG. 1).

If the packaging system of the invention has been conveniently realised,that is suitably choosing the capacity of the bottle, only one wash issufficient to transfer more than 99% of the active principle containedin said bottle. Always in optimal conditions, if two washes areperformed, practically 100% of the active principle is certainlytransferred.

The connectors used in combination with the packaging system of theinvention are known to the technique and available on the market, forexample sold by the company B. Braun Melsungen AG, Germany.

According to a preferred embodiment, said spikes have a length such thatthey do not penetrate much inside said bottles, to avoid leaving anyresidual volume of pharmaceutical composition mixed with solution forinfusion inside the bottle itself

The containers holding the liquid for infusion made of collapsiblematerial are known and marketed by many companies. These containers maybe in the shape of bags or bottles.

So, according to one of its aspects, the present invention concerns akit for the parenteral administration of drugs which comprises at least:

-   a) a container holding a fluid for parenteral infusion;-   b) a dosage unit comprising at least one pharmaceutical composition    in liquid form to be parenterally administered;-   c) a means for transferring the pharmaceutical composition from the    dosage unit (b) to the container (a);    characterised in that said at least one dosage unit is a packaging    system according to the invention.

According to the present invention, the term “parenteral administration”means any administration by an approach other than oral, and includesprincipally, but not only, intravenous administration.

The “container” referred to as component (a) is for example an infusionbag or a glass bottle and it contains a “fluid for parenteral infusion”which is a solution or a microemulsion for infusion, for example aphysiological solution containing salts, sugars, etc., or amicrosuspension, for example of the type for parenteral feeding, alladvantageously sterile.

The “container” of the invention also comprises the couplings, tubes,flow regulators, any filters or dosers, and all the material fortransferring the fluid for parenteral infusion, advantageously forintravenous infusion, such as needles, butterfly valve, etc.

According to the present invention, the term “means for transferring thepharmaceutical composition” indicates any instrument suited fortransferring the pharmaceutical composition from the dosage unit (b) tothe container (a). Preferably the means for transferring thepharmaceutical composition may be composed of a suitable coupling whichputs said dosage unit in communication with said container.

According to a particularly preferred aspect, said means fortransferring the pharmaceutical composition is a connector provided withat least two perforating spikes (known as spikes), suited to put theinside of the bottle directly in contact with the container holding theliquid for infusion.

The kit of the invention may also advantageously comprise disposablegloves and an illustrative leaflet, as well as labels giving thenecessary warnings for the health-care operator.

The fluid for parenteral infusion contained in the container (a) mustalso be compatible with the drug to be administered. For example, in thecase of drugs that do not tolerate infusion solutions with determined pHvalues or containing specific vehicles, the fluid for parenteralinfusion shall be suitably chosen so as to avoid all possibledegradation or alteration of the active principle.

It may therefore be understood that the kit of the invention, containingall the necessary parts for intravenous administration, suitably chosenaccording to the nature of the drug and of the pharmaceuticalcomposition to be administered, puts health-care personnel in conditionsin which they can work safely and quickly. According to one embodimentof the invention, the infusion fluid is a solution for intravenousinfusion and contains a solution for injection of 0.9% sodium chloride(saline solution) or 5% dextrose (glucose solution).

According to another embodiment of the invention, the kit comprises twocontainers (a) one of which contains a saline solution and the other aglucose solution as described above. This variation allows thehealth-care operator, if he wishes, to choose the infusion solution mostuseful for the treatment at that moment.

According to a particularly preferred embodiment the invention concernsa kit as defined above, wherein said pharmaceutical compositioncomprises tacrolimus as the active principle.

According to a particularly advantageous embodiment the inventionconcerns a kit as defined above, wherein said one dosage unit is abottle containing a pharmaceutical composition which comprises 5 mg oftacrolimus dissolved in 1 ml of solvent composed of 200 mg ofpolyoxyethylenated hydrogenated castor oil (HCO-60) and ethanol, forexample absolute ethanol or anhydrous ethanol USP 80.0% v/v, q.s. to 1ml, said bottles having a capacity comprises between 5 and 10 ml,preferably between 6 and 9 ml, advantageously of about 7 ml.

According to another advantageous embodiment the invention concerns akit as defined above, wherein said dosage unit is a bottle containing apharmaceutical composition which comprises from 0.1 to 0.5 mg of citricacid, preferably about 0.25 mg, and 5 mg of tacrolimus dissolved in 1 mlof solvent composed of 200 mg of polyoxyethylenated hydrogenated castoroil (HCO-60) and ethanol, for example absolute ethanol or anhydrousethanol USP 80.0% v/v, q.s. to 1 ml.

According to an advantageous embodiment the invention concerns a kitwhich comprises at least:

a) a container holding a fluid for parenteral infusion;

b′) a dosage unit in the form of a bottle with a capacity of about 7 ml,comprising at least one pharmaceutical composition composed of 5 mg oftacrolimus dissolved in 1 ml of solvent composed of 200 mg ofpolyoxyethylenated hydrogenated castor oil (HCO-60) and ethanol, forexample absolute ethanol or anhydrous ethanol USP 80.0% v/v, q.s. to 1ml.

c) a means for transferring the pharmaceutical composition from thedosage unit (b′) to the container (a).

According to an advantageous embodiment the invention concerns a kitwhich comprises at least:

a collapsible container for intravenous infusion containing 500 ml of asaline solution of 0.9% sodium chloride, catheter and butterfly needle,the whole being made of PE;

a bottle having a capacity of about 7 ml, containing a pharmaceuticalcomposition composed of 5 mg of tacrolimus dissolved in 1 ml of solventcomposed of 200 mg of polyoxyethylenated hydrogenated castor oil(HCO-60) and ethanol q.s. to 1 ml;

a connector with at least two perforating spikes;

a pair of disposal gloves for pharmaceutical use;

an illustrative leaflet concerning on the active principle tacrolimus.

According to another of its aspects, the invention concerns a method fortransferring a pharmaceutical composition into a solution forintravenous infusion, said method comprising:

engaging a container holding a liquid for intravenous infusion, made ofcollapsible material, on one end of a connector equipped with at leasttwo spikes, one of which penetrates inside the rubber cap of saidcontainer;

engaging a bottle of the packaging system of the invention, afterremoval of the metal cap usually present on top of the rubber cap,upside down, on the other end of the above-mentioned connector, causingthe perforation of the rubber cap;

applying a light pressure on the container in collapsible material tomake the liquid for infusion pass through the two spikes and allow saidbottle to be “washed out”;

optionally repeating the operation in the previous step.

According to a particularly preferred embodiment the invention concernsa method as defined above, wherein said pharmaceutical compositioncomprises tacrolimus as the active principle.

The invention also concerns the use of a packaging system as definedabove for intravenous administration of a pharmaceutical composition.

The packaging system of the invention may also be used for drugs thatrequire pre-dilution before being transferred into the container holdingthe liquid for infusion, for example docetaxel.

In the specific case of docetaxel, for example, the pharmaceuticalspeciality on the market comprises a bottle containing the activeprinciple in polysorbate 80 and a bottle containing a solvent with whichfurther to dilute the active principle before transfer into the liquidfor infusion. Dilution is carried out by the health-care personnel usinga syringe. The illustrative leaflet of the medicinal speciality clearlyspecifies the conditions for making the dilution, so that a precipitateis not formed by rubbing the walls of the bottle with the transferneedle, as the final solution is oversaturated. Once diluted, thepharmaceutical composition thus formed is normally lifted with a syringeand transferred into the container holding the liquid for infusion. Forthe reasons discussed above, the active principle is present in thespeciality in excess of more than 10%, even of 20%, with respect to thedeclared amount.

The present invention not only succeeds in overcoming the inconvenienceslinked with the transfer of the pharmaceutical composition into theinfusion container, but it also provides a pre-dilution system whichpreserves the health-care personnel from accidental contact with theneedle of the used syringe or from the possible precipitation of someactive principles which require said pre-dilution.

So, according to another of its aspects, the invention supplies a kitcomprising:

(i) a packaging system as defined above suitable for a pharmaceuticalcomponent comprising docetaxel,

(ii) a bottle containing the solvent or the mix of suitable solvents forpre-dilution of a docetaxel concentrate; and

(iii) means for pre-diluting the concentrate with the solvent or the mixof suitable solvents.

The above means (iii) include for example a syringe with a retractablesafety needle; a syringe with a shielded needle (guard) which isactivated with only one hand; a syringe with a plastic needle, suitablefor perforating rubber (safer than a steel needle); a syringe without aneedle but with a Luer-Lock type connection (male) or similar, coupledto a connector having a spike on one side (facing the bottle) and aLuer-Lock or similar connection (female) on the other side.

According to a particular embodiment of this aspect of the invention,the bottle (ii) is not present and said solvent or said mix of solventsfor pre-dilution are contained in the means (iii) in which said syringesare therefore pre-filled.

It this way it is possible for the health-care personnel to take andtransfer said solvent or said mix of solvents safely and at the sametime eliminate the risk of precipitation of the active principle.

As has been said, it has been demonstrated that the efficacy of transferdepends directly on the packaging system used, in particular on theratio between the volume of the pharmaceutical composition and the emptyvolume in the bottle.

For example, washing tests have been carried out on various types ofpackaging systems comprising a bottle containing a pharmaceuticalcomposition containing 5 mg of tacrolimus dissolved in 1 ml of solventcomposed of 200 mg of polyoxyethylenated hydrogenated castor oil(HCO-60) and ethanol, for example absolute ethanol or anhydrous ethanolUSP 80.0% v/v, q.s. to 1 ml.

In particular bottles containing the above composition but havingdifferent capacities were tested, that is bottles with capacity from 3to 15 ml.

In the test the washing-out manoeuvres described above were performedand the residual amount of tactrolimus in the bottle after one or twowashes was assessed.

The results of the test are shown below in TABLE I.

TABLE I Bottle Number [TAC] in Number [TAC] in capacity Quality of ofresidual of residual ml connection washes volume (*) washes volume (*) 3Not very stable One >8% Two >2% 5 Reasonably One >5% Two ~1% stable 7Very stable One <1% Two Traces 8 Very stable One <1% Two Traces 9 StableOne <1% Two Traces 10 Reasonably One <1% Two Traces stable 15 ReasonablyOne <1% Two Traces stable (*) concentration of tactolimus in theresidual liquid.

It is clear from the data given in the table that the optimal capacityof the bottle containing the pharmaceutical composition of tacrolimusdefined above is between 5 and 10 ml.

For the purposes of efficacy of washing out, even bottles with a largercapacity could be use, but in this case there is some loss in terms ofstability of connection.

The stability of connection factor is in fact equally important, sincethe difference in pressure is decisive for limiting the volume thatremains in the bottle and so it is fundamental for this connection to behermetic. The stability of connection is strongly influenced by theshape of the neck of the bottle and by its consequent capacity to adaptto the connector.

For this reason, in the test described above, with the same percentagecontent of active principle in the residual volume, that is in the verysmall volume of liquid that remains in the bottle, bottles with acapacity of less than 10 ml are preferable because they allow a morestable connection.

However, bottles with larger dimensions were also tested, up to 50 ml.These bottles have shown that they can achieve a sufficiently stableconnection and an adequate “wash-out” but, as is understandable, theycannot reasonably be considered appropriate for containing 1 ml ofpharmaceutical composition, also because in this way the possibility ofmaking and effective visual control is lost.

The bottles thus prepared and used in the test described above weresubjected to a stability test and the results showed a correct stabilityof the composition.

We have therefore shown how the packaging system described above, inparticular with reference to bottles containing a pharmaceuticalcomposition composed of 5 mg of tacrolimus dissolved in 1 ml of solventcomposed of 200 mg of polyoxyethylenated hydrogenated castor oil(HCO-60) and ethanol, for example absolute ethanol or anhydrous ethanolUSP 80.0% v/v, q.s. to 1 ml, said bottles having a capacity between 5and 10 ml, overcomes all the inconveniences of the prior art, above allconsidering the fact that at present the only pharmaceutical compositioncontaining tacrolimus available on the market is packed in an ampoule tobe opened by breaking the neck and to be transferred by taking it with asyringe.

It is clear that the kit of the invention also allows the possibility oflater connecting several packaging systems (bottles) of the invention tothe same infusion bag, thus making it possible, by means of a series ofcharges (washes), to arrive at the desired concentration of the drug inthe infusion bag easily and without risks for the health-care personnel.At present health-care operators often take doses of active principlefrom several bottles or ampoules, therefore using numerous syringes witha needle, in order to reach the specific concentration desired for agiven patient. The kit of the invention is therefore an importanttechnical progress in favour of safety in the health-care environment.

The advantages of the packaging system of the invention, in particularof the one containing tacrolimus examined above in detail, thereforeseem evident and confirm the important technical progress offered by theinvention.

Experimental Section

EXAMPLES Example 1 Kit for Intravenous Administration of Tacrolimus

A kit is prepared in the form of a pharmaceutical package containing

a collapsible container for intravenous infusion containing 500 ml of asaline solution of 0.9% sodium chloride, coupling and butterfly needle,the whole being made of PE;

a bottle having a capacity of about 7 ml, containing a pharmaceuticalcomposition composed of 5 mg of tacrolimus dissolved in 1 ml of solventcomposed of 200 mg of polyoxyethylenated hydrogenated castor oil(HCO-60) and ethanol q.s. to 1 ml;

a connector with at least two perforating spikes;

a pair of disposal gloves for pharmaceutical use;

an illustrative leaflet concerning on the active principle tacrolimus.

Examples 2-5

A kit in the form of a pharmaceutical package like the one in example 1may contain different types of pharmaceutical compositions such as:

Example 2

A pharmaceutical composition composed of 5 mg of anhydrous tacrolimusdissolved in 1 ml of solvent composed of 200 mg of polyoxyethylenatedhydrogenated castor oil (HCO-60) in dehydrated ethanol (USP 80.0% v/v)q.s. to 1 ml.

Example 3

A pharmaceutical composition composed of 5 mg of anhydrous tacrolimusdissolved in 1 ml of solvent composed of 200 mg of polyoxyethylenatedhydrogenated castor oil (HCO-60), 0.25 mg citric acid, in dehydratedethanol (USP 80.0% v/v) q.s. to 1 ml.

Example 4

A pharmaceutical composition composed of 5 mg of anhydrous tacrolimusdissolved in 1 ml of solvent composed of 200 mg of polyoxyethylenatedhydrogenated castor oil (HCO-60), 0.25 mg monohydrate citric acid, indehydrated ethanol (USP 80.0% v/v) q.s. to 1 ml.

Example 5

A pharmaceutical composition composed of 2.5 mg of anhydrous tacrolimusdissolved in 0.5 ml of solvent composed of 100 mg of polyoxyethylenatedhydrogenated castor oil (HCO-60), 0.125 mg monohydrate citric acid, indehydrated ethanol (USP 80.0% v/v) q.s. to 0.5 ml.

Example 6 Kit for Intravenous Administration of Docetaxel

A kit is prepared in the form of a pharmaceutical package containing

a collapsible container for intravenous infusion containing 500 ml of asaline solution of 0.9% sodium chloride and/or a solution of 5%dextrose, coupling and butterfly needle, the whole being made of PE;

a bottle having a capacity of about 24 ml, containing a concentratecomposed of 40 mg of docetaxel dissolved in 1 ml of polysorbate 80;

a pre-filled syringe containing 3 ml of a solution of 13% ethanol inwater;

a connector with at least two perforating spikes;

a pair of disposal gloves for pharmaceutical use;

an illustrative leaflet concerning on the active principle docetaxel.

Example 7

A kit in the form of a pharmaceutical package like the one in example 6may also contain a concentrate of docetaxel composed of 100 mg of activeprinciple in 2.5 ml of polysorbate 80 in a bottle having a capacity of60 ml and a pre-filled syringe containing 7.5 ml of a solution of 13%ethanol in water.

1. A packaging system comprising a pharmaceutical composition to beadministered in a liquid for intravenous infusion, wherein said systemis a bottle which comprises said pharmaceutical composition and an emptyvolume ranging from 80% to 99% of the total volume of the bottle andwherein said bottle has a capacity of more than 5 ml and saidpharmaceutical composition comprises as active principle tacrolimus in apharmaceutically acceptable oily vehicle.
 2. A packaging systemaccording to claim 1, wherein said bottle comprises an empty volumeranging from 80% to 95% of the total volume of the bottle.
 3. Apackaging system according to claim 1, wherein said bottle is made ofglass.
 4. A packaging system according to claim 1, wherein said bottlehas a capacity between 5 ml and 10 ml.
 5. A packaging system accordingto claim 1, wherein said bottle has a capacity between 6 and 9 ml.
 6. Apackaging system according to claim 1, wherein said bottle has acapacity of 7 ml.
 7. A packaging system according to claim 1, whereinsaid pharmaceutical composition comprises 5 mg of tacrolimus dissolvedin 1 ml of solvent composed of 200 mg of polyoxyethylenated hydrogenatedcastor oil (HCO-60) and ethanol q.s. to 1 ml.
 8. A packaging systemaccording to claim 7, wherein said ethanol is absolute ethanol oranhydrous ethanol USP 80.0% v/v.
 9. A packaging system according toclaim 5, wherein said pharmaceutical composition comprises 5 mg oftacrolimus dissolved in 1 ml of solvent composed of 200 mg ofpolyoxyethylenated hydrogenated castor oil (HCO-60) and ethanol q.s. to1 ml.
 10. A packaging system according to claim 9, wherein said ethanolis absolute ethanol or anhydrous ethanol USP 80.0% v/v.
 11. A packagingsystem according to claim 6, wherein said pharmaceutical compositioncomprises 5 mg of tacrolimus dissolved in 1 ml of solvent composed of200 mg of polyoxyethylenated hydrogenated castor oil (HCO-60) andethanol q.s. to 1 ml.
 12. A packaging system according to claim 11,wherein said ethanol is absolute ethanol or anhydrous ethanol USP 80.0%v/v.
 13. A packaging system according to claim 1, wherein said bottle isa container for pharmaceutical compositions closed with a rubber cap,said cap being able to be pierced with needles or conventional piercingspikes.